The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in anxiety, depression, pain, mental retardation, and addiction. The potent and selective noncompetitive mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP, 1) has been a critically important tool used to further elucidate the role of mGluR5 in these CNS disorders. In an effort to provide novel and structurally diverse selective mGluR5 antagonists, we previously described a set of analogues with moderate activity wherein the alkyne bond was replaced with an amide group. In the present report, extended series of both amide and alkyne-based ligands were synthesized. MGluR5 binding and functional data were obtained that identified (1) several novel alkynes with comparable affinities to 1 at mGluR5 (e.g., 10 and 20-23), but (2) most structural variations to the amide template were not well tolerated, although a few potent amides were discovered (e.g., 55 and 56). Several of these novel analogues show drug-like physical properties (e.g., cLogP range = 2-5) that support their use for in vivo investigation into the role of mGluR5 in CNS disorders.